The American Cancer Society recommends that the best way to find skin cancers early is to recognize changes in existing skin lesions or the appearance of new lesions by regular self-examination. One way to facilitate this routine examination of skin lesions would be the availability of an easy-to-use, non-invasive device that can scan the body in a relatively short time. Such a device could be utilized through the general physician's office or the dermatologist's office. Thus a novel tool that provides spatial, structural as well as biochemical information about tissue disease state is proposed directed initially towards skin cancer management. This revised proposal seeks to develop a handheld combined confocal Raman spectroscopy and confocal imaging device that, can provide real-time, morphologic as well as biochemical information of skin lesions, potentially identifying these lesions as normal, benign and malignant for diagnosis of the disease. Raman spectroscopy is a purely biochemical technique and yields little information about the tissue microstructure. Confocal imaging could provide spatial as well as structural information that together with confocal Raman spectroscopy could yield information about tissue structure as well as biochemistry allowing for complete diagnosis. Thus this proposal is focused on the development of a clinical, confocal Raman instrument with confocal imaging as well as bright-field imaging capability for the differential diagnosis of skin lesions by providing real-time, automated, non-intrusive spectral as well as spatial information about the tissue biochemistry as well as structure. The steps needed to implement such a device will be pursued independently. The specific aims of the proposed project are as follows;Specific Aim (1): Develop and test a compact handheld Raman probe with video imaging capability. Specific Aim (2) Develop and test a handheld confocal imaging device at video rate: Specific Aim (3): Develop and test an integrated handheld confocal Raman/scanning confocal imaging handheld device. Specific Aim (4): Test signatures of normal and malignant skin tissues in vivo. Specific Aim (5): Understand the basis and dynamics of the malignancy associated changes observed in malignant tissues in regions away from the disease. The pilot clinical studies planned in this proposal will be conducted at the Vanderbilt University Medical Center and the Vanderbilt Clinic. The development of the proposed work will have a significant impact on health care by providing the potential for complete disease management with a single compact, sensitive detection tool. With the success of this technique, this multi-modal instrument can be applied to other organ sites such as the prostate and ovary as well as other diseases impacting a broader field in medicine.